The aim of this project is to develop a gene transfer procedure to repair or replace neurotransmitter function in cognitively impaired individuals. The underlying premise is that gene transfer to the brain will protect against neuronal damage as well as counteract memory related deficits associated with lesions and age-related decline. The therapeutic potential of gene transfer for neurological disease is promising, yet substantial technical and theoretical problems remain to be solved before this technology can be seriously considered for clinical application. In this application, safe and efficient non-viral gene transfer systems will be studied as in the rat septum. Progress has recently been made to improve transfection efficiency of cationic lipid-plasmid delivery systems in vivo in our laboratories and several others. Challenges remaining include a full characterization of the in vivo gene expression profile in the rat septum, demonstration of cholinergic efficacy, and lack of toxicity. We have synthesized a new cationic lipid based on a disulfide approach that is capable of transfecting neuronal and glia cells in vitro and in vivo. Our results suggest some hypotheses that will be addressed in this grant, including: 1) that gene expression in the septum can be increased by decreasing the particle size of the vector, which should increase the distribution of the vector system and decrease the associated toxicity; and 2) that non-viral mediated transgene expression of nerve growth factor in the septum will increase the size of cholinergic neurons and restore presynaptic hippocampal cholinergic function in aged animals. [unreadable] [unreadable] [unreadable]